5KQL

Co-crystal structure of LMW-PTP in complex with 2-oxo-1-phenyl-2-(phenylamino)ethanesulfonic acid

Summary for 5KQL

• Entry DOI: 10.2210/pdb5kql/pdb
• Related: 5KQG 5KQM 5KQP
• Descriptor: Low molecular weight phosphotyrosine protein phosphatase, (1~{S})-2-oxidanylidene-1-phenyl-2-phenylazanyl-ethanesulfonic acid (3 entities in total)
• Functional Keywords: lmw-ptp, inhibitor, complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P24666
• Total number of polymer chains: 1
• Total formula weight: 20528.20

Authors

Wang, J.,Zhang, Z.-Y.,Yu, Z.-H. (deposition date: 2016-07-06, release date: 2016-10-12, Last modification date: 2023-10-04)

Primary citation

He, R.,Wang, J.,Yu, Z.H.,Zhang, R.Y.,Liu, S.,Wu, L.,Zhang, Z.Y.
Inhibition of low molecular weight protein tyrosine phosphatase by an induced-fit mechanism.
J.Med.Chem., 2016

PubMed Abstract: The low molecular weight protein tyrosine phosphatase (LMW-PTP) is a regulator of a number of signaling pathways and has been implicated as a potential target for oncology and diabetes/obesity. There is significant therapeutic interest in developing potent and selective inhibitors to control LMW-PTP activity. We report the discovery of a novel class of LMW-PTP inhibitors derived from sulfophenyl acetic amide (SPAA), some of which exhibit greater than 50-fold preference for LMW-PTP over a large panel of PTPs. X-ray crystallography reveals that binding of SPAA-based inhibitors induces a striking conformational change in the LMW-PTP active site, leading to the formation of a previously undisclosed hydrophobic pocket to accommodate the α-phenyl ring in the ligand. This induced-fit mechanism is likely a major contributor responsible for the exquisite inhibitor selectivity.

PubMed: 27676368
DOI: 10.1021/acs.jmedchem.6b00993

Experimental method

X-RAY DIFFRACTION (1.45 Å)